Serotonin Hypothesis Research Articles

Intraperitoneal injection of lipopolysaccharide prevents seizure-induced respiratory arrest in a DBA/1 mouse model of SUDEP.

ObjectiveSudden unexpected death in epilepsy (SUDEP) is the cause of premature death of 50% patients with chronic refractory epilepsy. Respiratory failure during seizures is regarded as an important mechanism of SUDEP. Previous studies have shown that abnormal serotonergic neurotransmission is involved in the pathogenesis of seizure‐induced respiratory failure, while enhancing serotonergic neurotransmission in the brainstem suppresses it. Because peripheral inflammation is known to enhance serotonergic neuron activation and 5‐HT synthesis and release, we investigated the effect of intraperitoneal lipopolysaccharide (LPS)‐induced inflammation on the S‐IRA susceptibility during audiogenic seizures in DBA/1 mice.MethodsAfter DBA/1 mice were primed by exposing to sound stimulation for three consecutive days, they were tested for seizure severity and seizure‐induced respiratory arrest (S‐IRA) induced by sound stimulation under different conditions. We determined the dose and time course of the effects of intraperitoneal administration of LPS on audiogenic seizures and S‐IRA. The effects of blocking TLR4 or RAGE receptors and blocking 5‐HT receptors on the LPS‐induced effect on S‐IRA were investigated. Statistical significance was evaluated using the Kruskal‐Wallis test.ResultsIntraperitoneal injection of LPS significantly had dose‐dependent effects in reducing the incidence of S‐IRA as well as seizure severity in DBA/1 mice. The protective effect of LPS on S‐IRA peaked at 8‐12 hours after LPS injection and was related to both reducing seizure severity and enhancing autoresuscitation. Blocking TLR4 or RAGE receptor with TAK‐242 or FPS‐ZM1, respectively, prior to LPS injection attenuated its effects on S‐IRA and seizure severity. Injection of a nonselective 5‐HT receptor antagonist, cyproheptadine, or a 5‐HT3 receptor antagonist, ondansetron, was effective in blocking LPS‐induced effect on S‐IRA. Immunostaining results showed a significant increase in c‐Fos‐positive serotonergic neurons in the dorsal raphe.SignificanceThis is the first study that demonstrates the effect of intraperitoneal LPS injection‐induced inflammation on reducing S‐IRA susceptibility and provides additional evidence supporting the serotonin hypothesis on SUDEP. Our study suggests that inflammation may enhance brainstem 5‐HT neurotransmission to promote autoresuscitation during seizure and prevent SUDEP.

Amino acids and acylcarnitines as potential metabolomic markers of schizophrenia: new approaches to diagnostics and therapy

Background. Schizophrenia is a socially significant mental illness with insufficiently studied etiology and pathogenesis. A number of hypotheses of schizophrenia pathogenesis (dopamine, glutamate, kinurenin and serotonin hypotheses) bring together the fact that amino acids are precursors or intermediate metabolic products of these metabolites. Amino acids and their metabolites play an important role as significant substrates and regulators in many metabolic pathways.The aim of this review is to analyze the literature data on the studies of amino acids and acylcarnitines in patients with schizophrenia.Methods. A literature search was conducted using PubMed databases for articles published in English and covering the period from the first articles on this topic, dated 1977 to April 2019. Combinations of the following keywords were used to search for “schizophrenia”, “antipsychotics” and “amino acids”, “acylcarnitines”, “metabolomics”.Results. The review summarizes the data on the content of amino acids and acylcarnitines in the peripheral blood of schizophrenia patients and their dynamics in the course of pharmacotherapy with antipsychotic drugs. The potential of determining amino acids as biomarkers of therapeutic response and side effects, as well as their use in the treatment of patients with schizophrenia, are considered.Conclusion. Further investigation of the spectrum of amino acids and their metabolites with the using of mass spectrometric methods of metabolic analysis can lead to the discovery of new therapeutic targets and strategies, assess their role in the pathophysiology of schizophrenia, identify mechanisms that ensure the development of antipsychotic antipsychotics, and drug-induced side effects antipsychotics, in particular, metabolic syndrome.

Olfactory bulbectomy and raphe nucleus relationship: a new vision for well-known depression model

Background/aim: The olfactory bulbectomy (OBX) technic is a well-known animal model for depression. According to serotonin hypothesis of depression, one of the possible explanations to this mechanism is the destroying effect of OBX on raphe nuclei which especially include serotonergic neurons. In this study, we aimed to explore histopathological findings in raphe nuclei in OBX rats.Materials and methods: Forty-eight rats (8 control group, 10 sham group, and 30 as the study group) were used. No procedure was applied to the control group. Only frontal burr holes were performed at the level of olfactory bulbs (OBs) on the sham group. Mechanical OBX by compression was applied to 20 rats and the OBs of 10 rats were cauterized. Their OBs, olfactory cortices, raphe nuclei were extracted, tissue specimens were taken than examined by using histopathological methods including hematoxylin and eosin, S-100, and TUNEL staining. Physical dissector method was used to evaluate the number of living and apoptotic neurons in the raphe nuclei.Results: Prominent neuronal loss and morphological changes in the dorsal raphe nuclei were detected in study groups.Conclusion: Raphe nuclei degeneration, related alterations in neurotransmitter system activities and functional brain connectivity might be related to neurobiology of depression.

Neural activity in the periaqueductal gray and other specific subcortical structures is enhanced when a selective serotonin reuptake inhibitor selectively prevents seizure-induced sudden death in the DBA/1 mouse model of sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a critical issue in epilepsy, and DBA/1 mice are a useful animal model of this devastating epilepsy sequela. The serotonin hypothesis for SUDEP proposes that modifying serotonergic function significantly alters susceptibility to seizure-induced respiratory arrest (S-IRA). Agents that enhance serotonergic function, including a selective serotonin reuptake inhibitor, fluoxetine, selectively prevent S-IRA in DBA/1 mice. This study examined fluoxetine-induced changes in brain activity using manganese-enhanced magnetic resonance imaging (MEMRI) to reveal sites in the DBA/1 mouse brain where fluoxetine acts to prevent S-IRA. DBA/1 mice were subjected to audiogenic seizures (Sz) after saline or fluoxetine (45mg/kg, intraperitoneal) administration. Control DBA/1 mice received fluoxetine or saline, but Sz were not evoked. A previous MEMRI study established the regions of interest (ROIs) for Sz in the DBA/1 mouse brain, and the present study examined MEMRI differences in the ROIs of these mouse groups. The neural activity in several ROIs was significantly increased in fluoxetine-treated DBA/1 mice that exhibited Sz but not S-IRA when compared to the saline-treated mice that exhibited both Sz and respiratory arrest. These structures included the periaqueductal gray (PAG), amygdala, reticular formation (sensorimotor-limbic network), Kölliker-Fuse nucleus, facial-parafacial group (respiratory network), and pontine raphe. Of these ROIs, only the PAG showed significantly decreased neural activity with saline pretreatment when seizure-induced respiratory arrest occurred as compared to saline treatment without seizure. The PAG is known to play an important compensatory role for respiratory distress caused by numerous exigent situations in normal animals. The pattern of fluoxetine-induced activity changes in the present study suggests that PAG may be the most critical target for fluoxetine's action to prevent seizure-induced sudden death. These findings have potential clinical importance, because there is evidence of anomalous serotonergic function and PAG imaging abnormalities in human SUDEP.

Fenfluramine, a serotonin-releasing drug, prevents seizure-induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP.

Prevention of sudden unexpected death in epilepsy (SUDEP) is a critical goal for epilepsy therapy. The DBA/1 mouse model of SUDEP exhibits an elevated susceptibility to seizure-induced death in response to electroconvulsive shock, hyperthermia, convulsant drug, and acoustic stimulation. The serotonin hypothesis of SUDEP is based on findings that treatments which modify serotonergic function significantly alter susceptibility to seizure-induced sudden death in several epilepsy models, including DBA/1 mice. Serotonergic abnormalities have also recently been observed in human SUDEP. Fenfluramine is a drug that enhances serotonin release in the brain. Recent studies have found that the addition of fenfluramine improved seizure control in patients with Dravet syndrome, which has a high incidence of SUDEP. Therefore, we investigated the effects of fenfluramine on seizures and seizure-induced respiratory arrest (S-IRA) in DBA/1 mice. The dose and time course of the effects of fenfluramine (i.p.) on audiogenic seizures (Sz) induced by an electric bell in DBA/1 mice were determined. Videos of Sz-induced behaviors were recorded for analysis. Statistical significance (P<0.05) was evaluated using the chi-square test. Sixteen hours after administration of 15mg/kg of fenfluramine, a high incidence of selective block of S-IRA susceptibility (P<0.001) occurred in DBA/1 mice without blocking any convulsive behavior. Thirty minutes after 20-40mg/kg of fenfluramine, significant reductions of seizure incidence and severity, as well as S-IRA susceptibility occurred, which were long-lasting (≥48hours). The median effective dose (ED50 ) of fenfluramine for significantly reducing Sz at 30minutes was 21mg/kg. This study presents the first evidence for the effectiveness of fenfluramine in reducing seizure incidence, severity, and S-IRA susceptibility in a mammalian SUDEP model. The ability of fenfluramine to block S-IRA selectively suggests the potential usefulness of fenfluramine in prophylaxis of SUDEP. These results further confirm and extend the serotonin hypothesis of SUDEP.

Regulation of dopamine neurotransmission from serotonergic neurons by ectopic expression of the dopamine D2 autoreceptor blocks levodopa-induced dyskinesia

Levodopa-induced dyskinesias (LID) are a prevalent side effect of chronic treatment with levodopa (L-DOPA) for the motor symptoms of Parkinson’s disease (PD). It has long been hypothesized that serotonergic neurons of the dorsal raphe nucleus (DRN) are capable of L-DOPA uptake and dysregulated release of dopamine (DA), and that this “false neurotransmission” phenomenon is a main contributor to LID development. Indeed, many preclinical studies have demonstrated LID management with serotonin receptor agonist treatment, but unfortunately, promising preclinical data has not been translated in large-scale clinical trials. Importantly, while there is an abundance of convincing clinical and preclinical evidence supporting a role of maladaptive serotonergic neurotransmission in LID expression, there is no direct evidence that dysregulated DA release from serotonergic neurons impacts LID formation. In this study, we ectopically expressed the DA autoreceptor D2Rs (or GFP) in the DRN of 6-hydroxydopamine (6-OHDA) lesioned rats. No negative impact on the therapeutic efficacy of L-DOPA was seen with rAAV-D2Rs therapy. However, D2Rs treated animals, when subjected to a LID-inducing dose regimen of L-DOPA, remained completely resistant to LID, even at high doses. Moreover, the same subjects remained resistant to LID formation when treated with direct DA receptor agonists, suggesting D2Rs activity in the DRN blocked dyskinesogenic L-DOPA priming of striatal neurons. In vivo microdialysis confirmed that DA efflux in the striatum was reduced with rAAV-D2Rs treatment, providing explicit evidence that abnormal DA release from DRN neurons can affect LID. This is the first direct evidence of dopaminergic neurotransmission in DRN neurons and its modulation with rAAV-D2Rs gene therapy confirms the serotonin hypothesis in LID, demonstrating that regulation of serotonergic neurons achieved with a gene therapy approach offers a novel and potent antidyskinetic therapy.

Genetic Association Study in Multigenerational Kindreds With Vasovagal Syncope: Evidence for Involvement of Sex-Specific Serotonin Signaling.

Several studies suggest that vasovagal syncope has a genetic origin, but this is unclear. We assessed whether plausible gene variants associate with vasovagal syncope. We studied 160 subjects in 9 kindreds comprising 82 fainters and 78 controls. The diagnosis was ascertained with the Calgary Syncope Score. Common genetic variants were genotyped for 12 genes for vascular signaling, potassium channels, the HTR1A(serotonin 5-HT1A receptor), SLC6A4(serotonin reuptake transporter), and COMT(catecholamine O-methyltransferase). Sex-specific associations between genotypes and phenotypes were tested. In 9 out of 12 variants, there was no significant association between genotype and phenotype. However, the HTR1A(-1019) G alleles associated with syncope in males, but not in females ( P=0.005). CC and GG males had 9% versus 77% likelihoods of syncope. The SLC6A4 promoter L alleles associated with decreased syncope in males but increased in females ( P=0.059). The LL and SS males had 25% and 47% syncope likelihoods, whereas females had 75% and 50% syncope likelihoods. The COMT c.472 A alleles associated with decreased syncope in males but increased in females ( P=0.017). The GG and AA males had 50% and 15% syncope likelihoods, whereas females had 52% and 73% syncope likelihoods. There is a sex-dependent effect of alleles of serotonin signaling and vasovagal syncope, supporting the serotonin hypothesis of the physiology of vasovagal syncope.

The serotonin hypothesis in pulmonary hypertension revisited: targets for novel therapies (2017 Grover Conference Series).

Increased synthesis of serotonin and/or activity of serotonin in pulmonary arteries has been implicated in the pathobiology of pulmonary arterial hypertension (PAH). The incidence of PAH associated with diet pills such as aminorex, fenfluramine, and chlorphentermine initially led to the “serotonin hypothesis of pulmonary hypertension.” Over the last couple of decades there has been an accumulation of convincing evidence that targeting serotonin synthesis or signaling is a novel and promising approach to the development of novel therapies for PAH. Pulmonary endothelial serotonin synthesis via tryptophan hydroxlase 1 (TPH1) is increased in patients with PAH and serotonin can act in a paracrine fashion on underlying pulmonary arterial smooth muscle cells (PASMCs), In humans, serotonin can enter PASMCs via the serotonin transporter (SERT) or activate the 5-HT1B receptor; 5-HT1B activation and SERT activity cooperate to induce PASMC contraction and proliferation via activation of downstream proliferative and contractile signaling pathways. Here we will review the current status of the serotonin hypothesis and discuss potential and novel therapeutic targets.

Anorexigen-Associated Pulmonary Arterial Hypertension and the Serotonin Hypothesis: A Story Worth Telling

Diet pills such as aminorex, fenfluramine, and dexfenfluramine have been strongly associated with the development of pulmonary arterial hypertension (PAH). Other drugs ostensibly related in function have also been implicated as “likely” associated, including amphetamine, methamphetamine, and the serotonin precursor L-tryptophan. Serotonin signaling is thought to be a mediator of diet pill–associated PAH, and it is also thought to potentially play a significant role in PAH in general. In this article, we review the evidence supporting the serotonin hypothesis in PAH in both contexts, and the potential concerns related to selective serotonin reuptake inhibitors and other medications acting on serotonin signaling pathways.

From Serotonin to Neuroplasticity: Evolvement of Theories for Major Depressive Disorder.

The serotonin (5-HT) hypothesis of depression has played an important role in the history of psychiatry, yet it has also been criticized for the delayed onset and inadequate efficacy of selective serotonin reuptake inhibitors (SSRIs). With evolvement of neuroscience, the neuroplasticity hypothesis of major depressive disorder (MDD) has been proposed and may provide a better framework for clarification the pathogenesis of MDD and antidepressant efficacy. In this article, we first summarized the evidence challenging the monoamine hypothesis and proposed that the antidepressant efficacy of SSRIs is not derived from elevated monoamine (5-HT, noradrenaline (NE), or dopamine (DA)) concentration or monoamine neurotransmission. Second, we reviewed the role of stress in the pathogenesis of MDD and gave a brief introduction to the neuroplasticity hypothesis of MDD. Third, we explored the possible mechanisms underlying the antidepressant efficacy of typical antidepressants in the context of neuroplasticity theory. Fourth, we tried to provide an explanatory framework for the significant difference in onset of efficacy between typical antidepressants and ketamine. Finally, we provided a brief summarization about this review article and some perspectives for future studies.

A current view on the history of atypical antipsychotics

Based on the analysis of the original literature, the author for the first time systemizes the data on the story of atypical antipsychotic drugs. The history of introduction of the first atypical neuroleptics - clozapine and sulpiride, which launched the dichotomic development of psychopharmacology of atypical antipsychotics, is described. Historical facts on the introduction into practice of different sulpiride- and clozapine-like neuroleptics as well as the relationship of their history with the elaboration of dopamine and serotonin hypotheses of mechanisms of action of antipsychotics are presented. The author analyzes the efficacy and tolerability of treatment with different atypical neuroleptics. An importance of evidence-based medicine principles in the history of atypical antipsychotics is described. A significance of the history of some atypical and typical (pericyazine) neuroleptics in the evolution of conceptions on the validity of evidence-based medicine in psychiatry is evaluated. Main stages in the history of typical and atypical antipsychotics are determined.

Rehabilitating LSD history in postwar America: Dilworth Wayne Woolley and the serotonin hypothesis of mental illness

Revisiting the history of postwar LSD (lysergic acid diethylamide) research illuminates how the work of a chemist at the Rockefeller Institute contributed to the development of a biochemical paradigm for mental functioning. Dilworth Wayne Woolley proposed one of the first theories of the biochemistry of mental illness based on empirical evidence. His research with LSD and serotonin had wide-ranging repercussions for pharmacology and fit neatly into the emerging medicalization of mental illness. Reevaluating Woolley’s ideas and the fruits of psychopharmacology leads to possible new approaches toward mental health and illness when considered alongside lessons learned from past research with psychedelic substances, and exemplifies a broader paradigm shift in cultural studies toward a biopsychosocial model that acknowledges the intersections between biology and culture.

Tobacco use is associated with reduced amplitude and intensity dependence of the cortical auditory evoked N1-P2 component.

Tobacco use is linked to cerebral atrophy and reduced cognitive performance in later life. However, smoking-related long-term effects on brain function remain largely uncertain. Previous studies suggest that nicotine affects serotonergic signaling, and the intensity dependence (alias loudness dependence) of the auditory evoked N1-P2 potential has been proposed as a marker of serotonergic neurotransmission. In the present study, we assesed the effects of chronic smoking on amplitude and intensity dependence of the auditory evoked N1-P2 potential. Subjects underwent a 15-min intensity dependence of auditory evoked potentials (IAEP) paradigm. From N = 1739 eligible subjects (40-79years), we systematically matched current smokers, ex-smokers, and never-smokers by sex, age, alcohol and caffeine consumption, and socioeconomic status. Between-group differences and potential dose-dependencies were evaluated. Analyses revealed higher N1-P2 amplitudes and intensity dependencies in never-smokers relative to ex- and current smokers, with ex-smokers exhibiting intermediate intensity dependencies. Moreover, we observed pack years and number of cigarettes consumed per day to be inversely correlated with amplitudes in current smokers. According to the IAEP serotonin hypothesis, our results suggest serotonin activity to be highest in current smokers, intermediate in ex-smokers, and lowest in never-smokers. To our knowledge, the present study is the first providing evidence for a dose-dependent reduction in N1-P2 amplitudes. Further, we extend prior research by showing reduced amplitudes and intensity dependencies in ex-smokers even 25years, on average, after cessation. While we can rule out several smoking-related confounders to bias observed associations, causal inferences remain to be established by future longitudinal studies.

The serotonin transporter in depression: Meta-analysis of in vivo and post mortem findings and implications for understanding and treating depression

BackgroundAltered serotonin transporter levels have been reported in blood and brain of patients with major depressive disorders. However, the strength and consistency of the evidence for altered serotonin transporter availability in major depressive disorder is not clear. MethodsTo address this, a comprehensive meta-analysis was conducted of all available in vivo neuroimaging and post mortem studies reporting serotonin transporter availability in patients with depression compared with healthy controls. ResultsThe final sample consisted of fifty (n=27 in vivo and n=25 post mortem) studies including 877 patients with depression (mean age: 42.9 years) and 968 healthy controls (mean age: 42.7 years). In vivo neuroimaging studies indicated reduced serotonin transporter binding in the striatum (g=−0.39, p=0.01), the amygdala (g=−0.37, p=0.01) and the brainstem (g=−0.31, p=0.01), including the midbrain (g=−0.27, p=0.02), but no significant alteration in the thalamus or the hippocampus. The post mortem findings indicated no significant change in serotonin transporter binding in depression in the brainstem (p=0.64), the frontal cortex (p=0.75) and the hippocampus (p=0.32, corrected for publication bias). Although there were too few studies for a meta-analysis, the post mortem studies in the amygdala and striatum showed reduced SERT binding in MDD in absolute terms, consistent with the imaging findings. LimitationsA number of potential factors might have biased the results of the present meta-analysis such as the imaging modality (post mortem or in vivo neuroimaging), partial volume effects, susceptibility of some radiotracers to synaptic serotonin levels or binding to other monoamine transporters. ConclusionsThe results indicate that serotonin transporter availability in depressed patients is reduced in key regions of the limbic system. This provides direct support for the serotonin hypothesis of depression, and underlines the importance of the serotonin transporter as a target of pharmacological treatments.

What has serotonin to do with depression?

The “serotonin hypothesis” of clinical depression is almost 50 years old. At its simplest, the hypothesis proposes that diminished activity of serotonin pathways plays a causal role in the pathophysiology of depression. This notion was based on the depressogenic effects of amine depleting agents such as reserpine, as well as the actions of antidepressant drugs such as monoamine oxidase inhibitors and tricyclic antidepressants, discovered by clinical serendipity, but later found in animal experimental studies to potentiate the effects of serotonin and other monoamines at the synapse (1). This pattern of theory making – moving from the pharmacological actions of drugs with some efficacy in treatment to biochemical notions of causation – has been common in biological psychiatry. In such an undeveloped field this approach, though logically precarious, has been a useful heuristic and, in the case of the dopamine hypothesis of psychosis, has been strikingly upheld by advanced brain imaging techniques (2). However, the serotonin hypothesis of depression has not been clearly substantiated. Indeed, dogged by unreliable clinical biochemical findings and the difficulty of relating changes in serotonin activity to mood state, the serotonin hypothesis eventually achieved “conspiracy theory” status, whose avowed purpose was to enable industry to market selective serotonin reuptake inhibitors (SSRIs) to a gullible public (3).

Serotonin and impulsive aggression.

Aggression is a behavior with evolutionary origins, but is often both destructive and maladaptive in today's society. Research over the past several decades has confirmed the involvement of neurotransmitter function in aggressive behavior. This research has centered around the "serotonin hypothesis." As this literature continues to grow, guided by pre-clinical research and aided by the application of increasingly sophisticated neuroimaging methodology, a more complex picture has emerged. As current pharmacological and therapeutic interventions are effective but imperfect, it is hoped that new insights into the neurobiology of aggression will reveal novel avenues for treatment of this destructive and costly behavior.

Revisiting the Serotonin Hypothesis: Implications for Major Depressive Disorders.

Major depressive disorder (MDD) is a heritable neuropsychiatric disease associated with severe changes at cellular and molecular levels. Its diagnosis mainly relies on the characterization of a wide range of symptoms including changes in mood and behavior. Despite the availability of antidepressant drugs, 10 to 30% of patients fail to respond after a single or multiple treatments, and the recurrence of depression among responsive patients is very high. Evidence from the past decades suggests that the brain neurotransmitter serotonin (5-HT) is incriminated in MDD, and that a dysfunction of 5-HT receptors may play a role in the genesis of this disease. The 5-HT membrane transporter protein (SERT), which helps regulate the serotonergic transmission, is also implicated in MDD and is one of the main targets of antidepressant therapy. Although a number of behavioral tests and animal models have been developed to study depression, little is known about the neurobiological bases of MDD. Understanding the role of the serotonergic pathway will significantly help improve our knowledge of the pathophysiology of depression and may open up avenues for the development of new antidepressant drugs. The overarching goal of this review is to present recent findings from studies examining the serotonergic pathway in MDD, with a focus on SERT and the serotonin 1A (5-HT1A), serotonin 1B (5-HT1B), and serotonin 2A (5-HT2A) receptors. This paper also describes some of the main molecules involved in the internalization of 5-HT receptors and illustrates the changes in 5-HT neurotransmission in knockout mice and animal model of depression.

Caffeine links dopamine and serotonin release during passive heat loading

Caffeine links dopamine and serotonin release during passive heat loading

Shooting the messenger: the neurobiology of depression

Depression is a very common disorder with both psychological and biological manifestations. The prevailing rationale for antidepressant drug treatment is the serotonin hypothesis, but this is no longer accepted as an adequate explanation for depressive disorder. The role of other neurotransmitters such as glutamate may be important, but there is much to be learned. This review considers current evidence for neurophysiological factors in depression, and implications for care and treatment.

Serotonin hypothesis and pulmonary artery hypertension

Pulmonary arterial hypertension (PAH) is a progressive, complex disease leading to the right ventricular failure and premature death. PAH is characterized by increased pulmonary arterial pressure, increased vascular resistance, pulmonary vascular remodeling and endothelial dysfunction. Pathomechanism of this disease is still unknown. It has been suggested, that endothelial dysfunction is caused by unbalance between vasodilators and vasoconstrictors e.g. serotonin (5-HT). Previously, serotonin hypothesis was linked to the anorexigens, derivatives of fenfluramine, which are serotonin transporter (SERT) substrates. Nowadays, it has been proved that all elements of serotonergic system within pulmonary circulation participate in the developement of PAH. The tryptophan hydroxylase 1 (Tph-1) catalyses synthesis of 5-HT from tryptophan in the pulmonary arterial endothelial cells. 5-HT mediates contraction of pulmonary vessels via 5-HT1B and 5-HT2A receptors. 5-HT is also transported into pulmonary arterial smooth muscle cells via SERT and through activation of reactive oxygen species and Rho-kinase may contribute to contraction or/and, via stimulation of transcription factors, lead to proliferation and remodelling. There is also increasing number of evidence about functional interaction between 5-HT1B receptor and SERT in modulation of vasoconstriction and proliferation in pulmonary arteries. This review discusses the role of 5-HT in the development of PAH and highlights possible therapeutic targets within serotonergic system.